Nu-propargyl sulfamides



United States Patent Ofiice 3,351,584 Patented Nov. 7,1967

3,351,584 N-PROPARGYL SULFAMIDES William J. Houlihan, Mountain Lakes, N.J., assignor to Sandoz Inc., Hanover, NJ. No Drawing. Filed July 17, 1964, Ser. No. 383,507 29 Claims. (Cl. 260-239) ABSTRACT OF THE DISCLOSURE This is a continuation-in-part of application Ser. No. 339,354, filed on Jan. 22, 1964, now abandoned, and of Ser. No. 375,288, filed on June 15, 1964, now Patent No. 3,320,314.

The present invention is directed to three classes of N-propargyl sulfamides of the formula R2 X so I/ a R I \H CECE wherein Each of R R R and R is, independently, either a hydrogen atom, (-H); lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, and butyl; lower alkoxy, e.g. methoxy, ethoxy, propoxy, isopropoxy, and butoxy; a fluorine atom (-F); or a chlorine atom (--Cl); preferably at least one of R R R and R being a chlorine atom;

Y is either hetero(mono)cyclic amino, the amino nitrogen of which is a ring nitrogen atom, e.g. aziridino,

pyrrolidino, piperidino, piperazino, azetidino, N'-(lower)alkyl-N-(piperazino, such as N-ethyl-N-piperazino, and morpholino; primary amino (-NH or Each of R and R is lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, and butyl; and

X is methylene (CH for one class of sulfamides;

dimethylene (-CH -CH for the second class of sulfamides; and trimethylene (--CH -CH CH for the third class of sulfamides.

The preparation of compounds (I) is accomplished by 7 heating at a temperature within the range of from about to about 250 C. and in a tertiary amine (a) secondary amine (II) and (b) sulfamide (III):

R s R4 2 R4 R: 2

i S0: N

E H R N H R r r N H N-SOzNH2 5 CH 5 OH (A) (II) (III) (Ia) To prepare compounds (I) wherein Y is other than primary amino, i.e. Y, a sulfamide (IV), e.g. N,N-dimethyl-N'-benzylsulfamide, is treated with 3-bromopro- For reaction (A) a temperature in excess of 50 C. is recommended, and a preferred range is from about to C., usually the reflux temperature of the system. Agitation may be employed during the reaction, but none is required.

The tertiary amine medium provides a solvent system in which the reaction takes place. Contemplated tertiary amines include, for example, tri(lower)alkylamines, e.g. triethylamine; (lower)alkyl pyridines, e.g. 3-ethyl pyridine; (lower)alkoxy pyridines, e.g. 2,5-di-methoxy pyridine; quinoline; (lower)alkyl quinolines, e .g. 8-ethyl quinoline; N-(lower) alkyl morpholine, eig. N-methyl morpholine; and N,N'-di(lower)alkyl piperazine, e.g. N- methyl-N'-ethyl piperazine.

Compounds (1) are useful as anticonvulsants and mild tranquilizers which may be administered either orally or parenterally. Oral dosage forms include tablets and capsules having standard fillers and other compounding constituents. The average daily dose may vary within the range of from 50 milligrams to 300 milligrams.

Throughout the disclosure each of the variables R R R R R R X, Y, and Y has its above-ascribed meaning unless otherwise indicated. Those compounds (I) wherein Y is primary amino are generally more active therapeutically than their counterparts wherein Y is Y, i.e. has another of the designated meanings for Y. Also, when one or more of R R R and R are chlorine atoms, the compounds are more active than the counterparts lacking chlorine atmos.

The processes for preparing compounds (I) are independent of the substituents on the benzene ring and of the meaning of X. Therefore, each of the examples is illustrative of all possible substitution on the benzene nucleus and for each meaning of X.

The following examples illustrate the invention, all temperatures being in degrees centigrade, the parts and per- 0 centages being by weight unless otherwise stated, and the relationship between parts by weight and parts by volume being the same as that between the kilogram and the liter.

Example 1. N-propargyl-N-benzylsulfamide CH S02 NH: (5H,.

ECH

In a flask equipped with a stirrer and a condenser attached to a bubble detector dissolve 12.9 parts (0.09 mole) of N-benzylpropargylamine and 7.2 parts (0.08 mole) of sulfamide in 100 parts by volume of pyridine. Stir and reflux the resulting solution until gassing is no longer detected in the bubble detector. Remove the solvent (pyridine) in vacuo on a rotary evaporator. Crystallize the viscous residue from methanol-Water. There are thus obtained 12 parts of N-propargyl-N-benzylsulfamide, melting point (M.P.) 116 to 118.

In similar manner by separately replacing the N-propargyl-N-benzylamine by an equivalent amount of each of:

N-propargyl-N-(3-chloro-2-fiuoro-4-is0propyl)- benzylarnine, N-propargyI-N- (4-chloro-3-fluoro-2-methoxy ,B-phenethylamine, N-propargyl-N- (2,3-dichloro-5-isopropoxy) -'yphenylpropylamine, N-propargyl-N-(2-chloro-3,5-difluoro)-benzylamine, N-propargyl-N- (2,4-dichloro-3-methoxy fi-phenethylamine, N-proparagyl-N-(2,5-dichloro-4-fluoro -'y phenylpropylamine, N-propargyl-N- 5-butyl-3,4-dichloro) -benzylamine, N-propargyl-N-2,3,4-trichloro-B-phenethylamine, N-propargyl-N-2,3,5-trichloro-'y-phenylpropylamine, N-propargyl-N- 3-methyl-2,4,5-trichloro) -benzylamine, N-propargyl-N-3,4,S-trichloro-B-phenethylamine, and N-propargyl-N-2,3,4,5-tetrachloro-'y-phenylpropylamine,

each of the corresponding compounds (I) is obtained.

Example 2.-N-pr0pargyl-N-3,4-dichlorobenzylsulfamide C1 rec-c5011 /N\ /NH2 CH2 SO:

In a flask equipped with a stirrer and a condenser attached to a bubble detector dissolve 10.7 par-ts (0.05 mole) of N-propargyl-3,4-dichlorobenzylamine and 4.8 parts (0.05 mole) of sulfamide in 75 parts by volume of pyridine. Stir and reflux the resulting solution until gassing is no longer detected in the bubble detector. Remove the solvent (pyridine) in vacuo on a rotary evaporator. Crystallize the viscous residue from methanol-water. There are thus obtained 26 parts of N-propargyl-N-3,4- dichlorobenzylsulfamide, M.P. 116 to 118".

In similar manner, by separately replacing the N-propargyl-3,4-dichlorobenzylamine by an equivalent amount of each of:

N-propargyl-N-2-chloro-/3-phenethylamine, N-propargyl-N-3-chlorow-phenylpropylamine, N-propargyl-N-4-chlorobenzylamine, N-propargy1-N-2,3-dichloro-B-phenethylamine, N-propargyl-N-2,4-dichloro-- -phenylpropylamine, N-propargyl-N-Z,5-dichlorobenzylamine, N-propargyl-N-(3,4-dichloro-2-methyl) 8- phenethylamine, N-propargyl-N-3,S-dichloro-'y-phenylpropylamine, N-propargyl-N-Z, 3,4-trichlorobenzylamine, N-propargyl-N-Z,3,S-trichloro-[i-phenethylamine, N-propargyl-N-2,4,5-trichloro-'y-phenylpropylamine, N-propargyl-N-3,4,5-trichlorobenzylamine, and N-propargyl-N-Z, 3,4,5 -tetrachloro-B-phenethylamine,

each of the corresponding compounds (I) is obtained.

Example 3A.-N-pr0pargyl-2,4-dichlo1'0-13- phenelhylamine c r-CEOH Example 3B.N-pr0pargy l-N-2,4-dichloro-fiphenethylsulfamide Cl C1 CHr-C E C H CHz-CHg-N S O 2NH;

In a flask equipped with a stirrer and a condenser attached to a bubble detector dissolve 13.2 parts (0.057 mole) of N-propargyl-2,4-dichloro-B-phenethylamine and 5.0 parts (0.052 mole) of sulfamide in 100 parts by volume of absolute pyridine. Stir and reflux the resulting solution until gassing is no longer detected in the bubble detector. Remove the solvent (pyridine) in vacuo on a rotary evaporator. Crystallize the viscous residue from diethyl ether-pentane. There are thus obtained 7.7 parts of N-propargyl N 2,4 dichloro-B-phenethylsulfamide, M.P. 88 to 90.

Example 4.N,N-dimethyl-N-propargyl-N'- benzylsulfamide To a solution of 3.0 parts (0.055 mole) of sodium methoxide in 200 parts of: dry methanol add 10.7 parts (0.05 mole) of N,N-dimethyl-N'-benzyl sulfamide. Place the solution in a rotary evaporator and then remove the solvent in vacuo until dryness. The crude sodium salt is then suspended in 150 parts of dry toluene and 15 parts of 7 dry dirnethyl formamide. Stir the obtained slurry, and add dropwise thereto a solution of 7.2 parts (4.75 parts by volume, 0.06 mole) of 3-bromopropyne in 150 parts by volume of dry toluene and 15 parts by volume of dry dimethylformamide. Stir the mixture overnight (about 17 hours) at room temperature (20). Filter oil the salts and concentrate the filtrate in vacuo on a rotary evaporator. Chromatograph the viscous residue in a column containing parts of alumina. Distill the chloroform eluate (4.0 parts) through a Claisen head to give 3.7 parts of N,N-dimethyl-N-propargyl-N'-benzylsulfamide of boiling point (B.P.) 144 to 145 at 0.2 mm.

In similar manner by separately replacing the N,N-dimetlhylf-N'-benzylsulfamide by an equivalent amount of eac o N ,N-diisopropyl-N"- 3,5 -dirne thoxy -7-phenylprop yl- A sulfamide,

N-methyl-N-isopropyl-N'- 3 -methyl--ethyl) -b enzylsulfamide,

N-pentamethylene-N- (4-chloro-3-fluoro-2-methoxy) -,B-

phenethylsulfamide,

N-dimethylene-N'-'y-phenylpropylsulfamide,

N-tetramethylene-N'- 3-chloro-2-fiuoro-4isopropyl benzylsulfamide,

N-hexamethylene-N- (2,3-dichloro-5-isopropoxy) -/3- phenethylsulfamide,

N- 3-aza) -tetramethylene-N'- (2-chloro-3,5-difiuoro -phenylpropyl-sulfamide,

N 3'-rnethylaza) -tetramethylene-N'- (2,4-dichloro-3- methoxy) -benzylsulfamide,

N- 3 -oxa) -tetramethylene-N- 2,5 -dichloro-4-fiu oro 8- phenethylsulfamide,

N-pentamethylene-N'- 5-butyl-3,4-dichloro) -'yphenylpropylsulfamide,

N-dimethylene-N'-2,3,4-trichlorobenzylsulfamide,

N-tetramethylene-N-2,3,5-trichloro-,B-phenethylsulfamide,

N-heXamethylene-N- 3-methyl-2,4,5-trichloro) -'yphenylpropylsulfamide,

N- (3 '-aza -tetramethylene-N-3,4,5-trichlorobenzyl sulfamide, and

N- 3 '-ethylaza -tetramethylene-N'-2,3,4,5-tetrachlorofl-phenethylsulfamide,

each of the corresponding compounds (I) is obtained.

It is thought that the invention and its advantages will be understood from the foregoing description. It is ap parent that various changes may be made in the structures .of compounds (I) without departing from the spirit and scope of the invention or sacrificing its material advantages. The examples merely provided illustrative embodiments.

What is claimed is: 1. A compound of the formula wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

2. N-propargyl-N-3,4-dichlorobenzylsulfamide.

3. N-propargyl-N-benzylsulfamide.

4. A compound of the formula (lower alkyl) R CH -NS Qr-N Hg (lower alkyl) R -H ECH wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

5. N,N-dirnethyl-N'-propargyl-N'-benzylsulfamide.

6. A compound of the formula Hg CHE-CH1 EOH wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom, and a chlorine atom.

8. A compound of the formula GEM-CH /CH CHk-CH,

CHr-CH 0-H;

wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom, and a chlorine atom.

9. A compound of the formula wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom, and a chlorine atom.

10. A compound of the formula wherein H2 R3 H (55011 wherein:

each of R R R and R is, independently, a memher selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoXy, a fluorine atom and a chlorine atom, and

Y is a member selected from the group consisting of aziridino, pyrrolidino, piperidino, piperazino, azetidino, N-(lower) alkyl-N-piperazino and morpholino. 12. A compound of the formula wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom, and a chlorine atom.

13. N-propargyl-N-2,4-dichloro-fi-phenethylsulfamide.

14. N propargyl N 2,4,6 trichloro ,8 phenethylsulfamide.

15. A compound of the formula (lower alkyl) R2 CH2'-CH3-NS Or-N Hz (lower alkyl) R -H EC H t.

wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

16. A compound of the formula CH3 CHTCH: R H

EOH t.

wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

17. A compound of the formula wherein each of R R R and R is, independently a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

18. A compound of the formula CHrCHr-CH;

R CHnCH5N-S O z-N H1 CHr-CHz-CH: R H

CECH wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

19. A compound of the formula wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

5 2 0. A compound of the formula l GHQ-CH1 R CHr-CH3N-SOz-N -R Hg CHr-CH: 10 R3 l CECE L.

wherein:

R is a member selected from the group consisting of a hydrogen atom and lower alkyl, and each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom. 21. A sulfamide of the formula wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

23. A compound of the formula (lower alkyl) R CH CHz-CHz-NSO -N CH: (lower alkyl) wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

24. A compound of the formula wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

25. A compound of the formula wherein each of R R R and R is, independently, a

member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

26. A compound of the formula wherein each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom and a chlorine atom.

27. A compound of the formula wherein each of R R R and R is, independently, a

member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkox chlorine atom.

y, a fluorine atom, and a R is a member selected from the group consisting of a hydrogen atom and lower alkyl, and each of R R R and R is, independently, a member selected from the group consisting of a hydrogen 15 atom, lower alkyl, lower alkoxy, a fluorine atom, and

a chlorine atom. 29. A sulfamide of the formula CECH wherein:

each of R R R and R is, independently, a member selected from the group consisting of a hydrogen atom, lower alkyl, lower alkoxy, a fluorine atom, and a chlorine atom, and

Y is a member selected from the group consisting of aziridino, pyrrolidino, piperidino, piperazino, azetidino, N-(lower) alkyl-N-piperazino and morpholino.

No references cited.

ALTON D. ROLLINS, Primary Examiner. 

1. A COMPOUND OF THE FORMULA
 21. A SULFAMIDE OF THE FORMULA
 29. A SULFAMIDE OF THE FORMULA 